Project Summary This project proposes to investigate the genetics of chronic obstructive pulmonary disease (COPD) using germline DNA linked to electronic health records (EHR) to discover new insights into the pathogenesis of the disease. COPD is the third leading cause of mortality worldwide and in the U.S., affecting 6.3% of the U.S. population. COPD is difficult to diagnose and highly heterogeneous in its presentation, with individuals experiencing different symptoms, complications, and outcomes. We intend to fill key gaps in our knowledge about COPD with this project. We hypothesize that combining a strategy that interrogates clinical characteristics (phenotypes) in the EHR of a large population with in-depth genomic analysis of the germline DNA will allow us to make a significant contribution to understanding the genetic factors associated with COPD. While various mechanisms for development and progression of COPD have been proposed, the biological mechanisms remain poorly understood. Genome-wide association studies have uncovered genetic associations with COPD, but there is little information about the biological pathways affected by these variants. By testing the association between multiple variants or gene expression and COPD, we hope to gain greater insights into the pathogenesis of this disease. Vanderbilt University Medical Center (VUMC) is an ideal location for Ms. Martucci's training given the unique resources available. VUMC has developed a de-identified EHR with over 2.1 million adult participants, with 220,000 individuals providing germline DNA. Over 22,000 individuals have had their DNA genotyped using the Illumina MEGA genome-wide array. By leveraging bioinformatics tools, this project will develop an algorithm for COPD within EHR, build genetic risk scores for COPD, and identify gene expression changes associated with COPD. Ms. Martucci will be mentored by experts in the fields of pulmonary disease and genetic epidemiology (Dr. Melinda Aldrich) and statistical genetics (Dr. Nancy Cox). In Aim 1, we will build an algorithm to identify COPD within the Vanderbilt EHR. Aim 2 will focus on building genetic risk scores for COPD and related phenotypes to investigate COPD pathogenesis and heterogeneity. In Aim 3, we will investigate gene expression changes associated with COPD and reduced lung function. The planned project will provide novel information that has the potential to lead to precision medicine discoveries for disease prevention, diagnosis, and management. The integrated rigorous research and clinical training experience gained from this career development award will enhance Ms. Martucci's potential to develop into a productive independent physician-scientist with a focus on biomedical research in pulmonary disease.